Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity

A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain–derived class II–associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes–associated β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-Ag7. These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within β cell secretory granules. Rapid CLIP dissociation enhanced the presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen-processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.

Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Ito, Y., Ashenberg, O., Pyrdol, J., Luoma, A. M., Rozenblatt-Rosen, O., Hofree, M., Christian, E., Ferrari de Andrade, L., Tay, R. E., Teyton, L., Regev, A., Dougan, S. K., Wucherpfennig, K. W. Tags: Autoimmunity Articles Source Type: research